PL89096B1 - - Google Patents

Description

The subject of the invention is a process for the preparation of new derivatives of substituted piperine oximes. dynoalkanones, in particular the oxime derivatives 4-diphenylmethyl-, 4 - / <* - hydroxy-α-phenylben- zyl / - and 4-diphenylmethylene piperidine alkanone, which serve as antihistamines, anti allergic and bronchodilators.

The new substituted piperidine derivatives have the general formula 1 where R is hydrogen or a hydroxyl radical; R1 is hydrogen or R and R1 together represent a second bond between atoms coal; n is an integer with the value 1-3; Z represents a thienyl radical, a phenyl radical or a radical phenyl substituted in the ortho, meta or para position with a halogen atom, such as chlorine, fluorine, bromine or iodine, straight or branched lower alkyl group of 1-4 carbon atoms, lower alkoxy group of 1-4 carbon atoms, lower dialkylamino or saturated single ring heterocyclic group such as pyrrolidine, piperidine, morpholine or N-lower alkylpiperazine. It is also within the scope of the invention the pharmaceutically acceptable acid addition salts and the individual optical isomers of the compound of Formula 1.

As can be seen from formula 1, the compounds according to the invention are derivatives 4-diphenylmethylpiperidine of the general formula 2, 4- (α-hydroxy-α-phenylbenzyl / piperidine derivatives of the general formula 3 and the 4-diphenylmethylene piperidine derivatives of the general formula 4. In the formulas n and Z have the meaning given above.

The term "lower alkyl" denotes a straight or branched alkyl radical of M atoms coal. An example of such lower alkyl groups in the compounds of the formulas 1-4 are present as direct intermediate substituents or in dialkylamino groups or in N-alkylpiperazine, in case Z is substituted phenyl radical, there are, for example: methyl, ethyl, n-propyl, n-butyl, isopropyl radicals, isobutyl and tertiary. butyl.

The preferred compounds according to the invention are those of the formulas 3 and 4, v which n and Z have the meaning given above, corresponding to general formula 5. They are characterized by the best antihistamine, antiallergic and bronchodilating properties.

Moreover, these compounds have no effect on the vascular nervous system and do not have a depressive effect. 89 096 In formula 5, R2 is a hydroxyl radical; R3 is hydrogen or R2 and R3 together form the second bond between carbon atoms, and n and Z have the meaning given above.

The compounds of formula V in which n is equal to 3 are more preferred.

Also included within the scope of the invention are the pharmaceutically acceptable acid addition salts and isomers geometrical relationships with the above formulas. These include salts with inorganic and organic acids with others, e.g. hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid; salts with carboxylic acids, e.g. acetic, propionic, glycolic, lactic, pyruvic, malonic, amber, fumic red, apple, wine, lemon, ascorbic, maleic, hydroxymaleic, dihydro ximalein, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic acid, cinnamon, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and salts with sulfonic acids, e.g. methanesulfonic, ethanesulfonic, O-hydroxyethanesulfonic phonbwym, and the like.

Examples of compounds obtained by the method according to the invention are, inter alia: oxime 4 * -fluo- ro-4- / 4-diphenylmethylene-piperidine / butyrophenone, 3- / 4-diphenylmethylene-piperidine oxime / -1- / 2-thiene- Io / propanone-1, 4- / 4-diphenylmethylene-piperidine / butyrophenone oxime, 4 'ethyl-4/4-diphenylmethate oxime tylopiperidine / butyrophenone oxime 4'-fluoro-4- / 4- / α-hydroxy-α-phenylbenzyl [piperidine] butyrophenone, 4'-fluoro-3- (4-) oxime hydroxy-α-phenylbenzyl / piperidine / propiophenone oxime, 4- (4-) α-hydroxy-α-phenyl- oxime benzyl / piperidine / -4 'piperidinobutyrophenone, 4'-bromo-4 - / - 4 / a-hydroxy-a-phenylbenzyl / pi- peridine / butyrophenone, 2- / 4-diphenylmethylpiperidine / acetophenone oxime, 4'-ethyl-3- / 4- / α-hydroxide sy-a-phenylbenzyl / piperidine / propiophenone, 4'-diisopropylamino-4- / 4 / a-hydroxy-a-phenyl- oxime benzyl (piperidine) butyrophenone oxime 4M isopropyl 4- (4-) a-hydroxy-a-phenylbenzyl / piperidine / butyrophenone phenone, 4'-tertiary-butyl-4- / 4- / a-hydroxy-a-phenylbenzyl / piperidine / butyrophenone oxime, oxime 4- (4-diphenylmethylene piperidine) -4'-methoxybutyrophenone and the like.

New compounds with use as antihistamines, antiallergic and dilating agents the bronchus can be used alone or with appropriate pharmaceutical carriers, in solid or liquid form, e.g. in the form of tablets, capsules, powders, solutions, suspensions or emulsions.

The compounds may be administered doustrieally, parenterally, e.g. subcutaneously, intravenously, intramuscularly, intrathecally; by instillation into the nose or into mucous membranes, such as the nose, throat, bronchial tubes, in the form of a liquid or solid aerosol.

The amount to be used new compounds can vary widely depending on the patient and the method of administration and is for a single dose from 0.01 to 20 mg per kilogram body weight. For example, for obtain the desired antihistamine, antiallergic or bronchodilating effect tablets containing 1 to 50 mg of the new compound can be used, given 1-4 times a day.

Permanent pharmaceutical forms are standard forms. These can usually be gelatin capsules containing new compounds and suitable carriers, e.g. lubricants and inert fillers such as lactose, sucrose, starch corn and the like. You can also use tablets containing new compounds with the usual bases pharmaceuticals, e.g. lactose, sucrose, corn starch and the like, in combination with binding agents such as acacia, corn starch or gelatin, disintegrants such as corn or potato starch, or alginic acid, and lubricants such as stearic acid or magnesium stearate.

The novel compounds can also be administered by injection, obtained by dissolution or suspension in pharmaceutically acceptable diluents with added carriers. It can be a barren solution formations in water or in oils, with or without the addition of surfactants and other acceptable in the pharmacy of adjuvants. Mineral, animal, vegetable or synthetic oils such as oil can be used peanut, soy, mineral and the like. It is generally advantageous to use as injection solutions solutions in water, saline, aqueous solutions of dextrose and related sugars, solutions in ethanol or in glycols such as propylene or polyethylene glycol.

Solutions or suspensions can be used in the form of aerosols by packing them in pressure containers including a gaseous or liquefied spraying agent, e.g. dichlorodifluoromethane, alone or in mixture with dichlorodifluoroethane, carbon dioxide, nitrogen, propane and the like; with the addition of the usual adjuvants, e.g. other solvents or wetting agents, as may be necessary or desirable.

It is also possible to use non-pressure forms by using atomizers for this purpose.

Hard gelatine capsules may have, for example, the following composition: a) 4'-III-tert-butyl-4- (4- (a-hydroxy-a-phenylbenzyl) oxime hydrochloride - piperidine / butyrophenone 10 mg89 096 3 b) talc 5 mg c) lactose 100 mg The dry powdered substances a and b are passed through a fine sieve, mixed well with lactose and dosed at 115 mg into hard gelatin capsules.

The tablets may have, for example, the following composition: a) oxime hydrochloride 4MII-tert-butyl4 (- / 4- (a-hydroxy-aphenylbenzyl) piperidine / butyrophenone 5 mg b) starch 43 mg c) lactose 60 mg d) 2 mg magnesium stearate Granules obtained by mixing lactose, compound a and part of starch and granulated then with paste starchy, dried, sieved and mixed with magnesium stearate. The mixture is tabletted to give tablets with a weight of 110 mg.

An aerosol booster solution may have, for example, the following composition: % by weight a) oxime hydrochloride 4- (4- (a-hydroxy-a-phenylbenzyl) piperidino / -4'-dimethylaminobutyrophenone 5.0 b) ethanol 35.0 c) dichlorodifluoromethane 60.0 The substances a, b and c are packed in a 15 ml stainless steel container, supplied with portions of 0.2 g of the preparation, which correspond to 10 mg of the compound a.

The suspension for preparing an aerosol may have, for example, the following composition: % by weight a) oxime hydrochloride 4'-fluoro-4- (4- (a-hydroxy-a-phenylbenzyl) piperidine / butyrophenone (particle size less than 10 µl) 20.0 b) triolein orbitol 0.5 c) dichlorodifluoromethane 39.75 d) dichlorodifluoroethane 39.75 Substances a, b, c and d are packed in 15 ml stainless steel containers supplied with a dosing valve in doses of 50 mg of the preparation, corresponding to 10 mg of compound a.

The suspension for intramuscular injection is prepared, for example, as follows: % by weight a) 4- / 4-diphenylmethylene-piperidine / -4'-di oxime hydrochloride methylaminobutyrephonone (particle size not greater than 10 / s) 1.0 b) polyvinylpyrrolidone, MW 25,000 0.5 c) lecithin 0.25 d) water for injection up to 100.0 Substances a, b, c and d are mixed, homogenized and 1 ml each into the ampoules, which are closed and uncovered in an autoclave at 121 ° C for 20 minutes. Each ampoule contains 10 mg / ml of compound a.

The usefulness of the new compounds is illustrated by the table below that shows the number of selected compounds required 50% inhibition of urticarial tubule induced in guinea pigs intradermal injection of 17hist- nina. Said compounds were injected 1 hour after the administration of histamine.

Example J Compound Ed 50 mg / kg I oxime hydrochloride 4, -fluoro-4- / 4- / a-hydroxy-a-phenyl- benzyl / piperidine / butyrophenone 5.4 II oxime hydrochloride 4, -bromo-4- / 4- / a-hydroxy-a-phenyl- benzylpiperidine / butyrophenone, 15.4 III oxime hydrochloride 4'-III-tert-butyl4- (4-) a-hydroxy-a-phenyl- benzyl / piperidine / butyrophenone 6.2 The smallest amounts of compounds from examples I - III necessary for the inhibition caused by spraying phtigene, bronchospasm and death in guinea pigs are 2 mg per kilogram when administered orally body pgi. Moreover, the compound of example III, at a concentration of 2x 10 "7 moles, inhibits the histamine-induced contraction Isolated mole intestine of guinea pigs.

The numbers in the table correspond to those in the examples below.

The compound of formula 1 can be prepared by the process of the invention by treating a hydroxylamine salt with Na 4 89 096 the appropriate substituted arylopiperidine alkyl ketone according to Scheme 1. In the formulas in Scheme 1, R, R 1, n and Z are as defined above and NH2OH.X is an acid addition salt, e.g. hydrochloride or hydroxylamine sulfate.

These reactions can be carried out in lower alcohols or in water, or in a mixture of them, in their presence an inorganic base such as sodium hydroxide, potassium hydroxide, sodium acetate and the like, or the presence of an organic base, e.g. pyridine. The reaction time is 1 to 8 hours, the temperature is 100 ° C.

Depending on the amount of base used, its strength and the method used for isolation, the compound of formula 1 in free base or acid addition salt form, according to the examples provided hereinafter.

Substituted aryl piperidinealkyl ketone derivatives of formula VI can be obtained by reaction alkylation of the corresponding substituted piperidine derivatives with the c1-haloalkyl ketone derivatives aryls, carried out in alcohols, ketones or hydrocarbons, in the presence of a base.

Example I. 4'-fluoro-4- [4- (α-hydroxy-α-phenyiobenzyl / piper-) oxime hydrochloride dyno] butyrophenone.

A mixture of 15.1 g (0.035 mol) 4'-fluoro-4- [4- (α-hydroxy-α-phenylbenzyl / piperidine] butyrophenone) and 15 g (0.216 mol) of hydroxylamine hydrochloride in 150 ml of pyridine are heated in a water bath 1.5 hours. After the solvent has been evaporated under reduced pressure, 150 ml are added to the residue water and 200 ml of methanol and the resulting solution is concentrated to 200 ml. The precipitate formed on cooling recrystallizes from methanol. The title compound is obtained with a melting point of 140-150 ° C.

Example II, 4'-bromo-4- [4- (α-hydroxy-α-phenylbenzyl / piperidine] butyridine) oxime hydrochloride rofenone.

10 g (0.02 mol) are added to 25 g of hydroxylamine hydrochloride dissolved in 150 ml of water 4'-bromo-4- [4- (α-hydroxy-α-phenylbenzyl) piperidine] butyrophenone hydrochloride. 100 ml of a 10% solution sodium hydroxide and 1100 ml of ethanol. The mixture is heated in a water bath within one hour the solvent is then evaporated off under reduced pressure. The residue recrystallizes from alcohol isopropyl to give the title compound, mp 217-219 ° C.

Example III. 4'-III-tert-butyl-4- [4- (α-hydroxy-α-phenylbenzyl / piper-) oxime hydrochloride dyno] butyrophenone.

A mixture of 15 g (0.03 mol) of 4'-tert-butyl-4- [4 "/ a_hy (I-hydroxy-α-phenylbenzyl / piperine) hydrochloride Dynoibutyrophenone and 15 g of hydroxylamine in 120 ml of pyridine are heated in a water bath for 4.5 hours.

After removing the pyridine under reduced pressure, the residue dissolves in a minimum amount of methanol and poured into an excess of ice-cold 10% hydrochloric acid. The precipitate is filtered off, washed with water and recrystallized from isopropyl alcohol to give the title compound, mp 160-172 ° C.

Example IV. 4'-III-order-butyl-4- [4- (α-hydroxy-α-phenylbenzyl / piperidine] butyrophen oxime nu.

A mixture of 15 g (0.03 mol) of 4'-Tertiary-butyl-4 [-4] -hydroxy-a-phenylbenzyl / piperine hydrochloride dyno] butyrophenone is heated with 15 ml of hydroxylamine hydrochloride in 120 ml of pyridine, in a water bath, while mixing, within 4 hours. After cooling to room temperature, the pyridine is evaporated under reduced pressure in a water bath and the residue is rubbed with a dilute hydroxide solution sodium chloride and then extracted with chloroform. The chloroform solution is washed with water and dried over anhydrous aqueous magnesium sulfate, sludge and sludge. The residue is triturated with hexane, and the precipitate is filtered off with suction and recycle crystallizes from ethanol to give the desired product, mp 211-213 ° C.

Example V. By repeating the procedure of example I, but replacing 4'-fluoro-4- [4- / a-hydroxy- sy-a-phenylbenzyl / piperidine] butyrophenone appropriate amount of 4'-ethyl-3 - [(4-diphenyl-methylene) piperidine] propiophenone or 4'-fluoro-2- [4- (diphenylmethyl) piperidine] acetophenone gives the hydrochloride 4 * -ethyl-3- / 4-diphenylmethylene piperidine / propiophenone and 4'-fluoro-2- / 4-diphenyl oxime hydrochloride lmethylpiperidine / acetophenone.

By repeating the procedure of example IV but replacing 4'-III-tertiary-butyl-4- [4- / a-hydro x-α-phenylbenzyl / piperidine] butyrophenone with the appropriate amount of the compounds listed in Table I obtained the following products are available.

Example No. Starting compound Product VI 4- [4 / α-hydroxy-cc-phenyloxime 4- [4- / α-hydroxy-α-phenyl- hydrochloride benzyl / piperidine] -butyrophenone, temperature benzyl / piperidine] butyrophenone mp 193.5-195 ° C VII 4- [4- / α-hydroxy-α-phenyloxime 4- [4- / α-hydroxy-α-phenyl- hydrochloride benzyl (piperidine] -1- (2-thienyl) -butane-benzyl / piperidine] -1- (2-thienyl) nu-1, m.p. 192.5-193.5 ° C butanone-189 096 5 VIII 4- [4- / α-hydroxy-α-phenyloxime 4- [4- / α-hydroxy-α-phenyl- hydrochloride benzyl / piperidine] -4'-methylbutyrophenone, benzyl / piperidine] -4'-methyl- mp 236-237 ° C butylphenone IX 4- [4-1a-hydroxy-α-phenylbenzyl / piperoxime 4 '- [4- / α-hydroxy - <* - phenyl- dyno] -4'-piperidinobutyrophenone, benzyl / piperidine] -4'-pipe- mp 137.5-139 ° C of ridinobutyrophenone X 4'-fluoro-2- [4- / a-hydroxy-a-phenylenoxime hydrochloride 4'-fluoro-2- [4- / a-hydro l-benzyl / piperidine] acetophenone, x-a-phenyl-benzyl / piperidine] mp 171-174 ° C acetophenone XI 4-fluoro-3- [4- (a-hydroxy-a-phenylbenzyl / pi-oxime 4'-fluoro-3- [4 - / (* - hydro peridine] propiophenone, mp 250 ° C xy-crphenylbenzyl-piperidine] acetophenone ryidine] acetophenone XII 4- / 4-diphenylmethylpiperidine / butoxime 4- / 4-diphenylmethylpiperidine hydrochloride of tyrophenone, mp 163.5-164.5 ° C of dyno / butyrophenone XIII 4'-fluoro-4- / 4-diphenylmethylpiperoxime hydrochloride 4'-fluoro-4- / 4-diphenylmethyl- dyno / butyrophenone, melting point 194-195.5 ° C lopiperidine / butyrophenone XIV 4'-fluoro-4- / 4-diphenylmethylene-piperoxime hydrochloride A'-fluoro-4- / 4-diphenylmethyl- ryidine / butyrophenone, melting point 190-191 ° C nopiperidine / butyrophenone _: _ _ XV 474-diphenylmethylene-piperidine hydrochloride (-1-) ''. 4- / 4-diphenylmethylene-piper oxime 2-thienyl / 1-butanone, melting point of dyno (-1- (2-thienyl) -butanone-1 132.5-134.5 ° C XVI 4- / 4-diphenylmethylene-piperidine / butoxime 4- / 4-diphenylmethylene-piper hydrochloride of tyrophenone, m.p. 160-161.5 ° C of ridine / butyrophenone XVII 4, -bromo-4- / 4-diphenylmethylene-piperoxime hydrochloride 4'-bromo-4- / 4-diphenylmethyl- dyno / butyrophenone, mp 228-230 ° C, nopiperidine / -butyrophenone XVIII hydrochloride * 4MII-tert-butyl-4- / 4-diphenylmethoxime 4'-III-tier-butyl-4- / 4-diphenyl- Tylenopiperidine / Butyrophenone, Methylene piperidine / Butyrophenone Temperature mp 223.5-225.5 ° C Example XIX. Oxime 4'-dimethylamino- [4- (ft-hydroxy-α-phenylbenzyl / piperidine] butyropheno- nu.

Up to 8 g (0.017 mol) of 4M dimethylamino-4- (a-hydroxy-a-phenylbenzyl / piperidinobutyrophenone approx. 150 ml of pyridine is added a fourfold excess of hydroxylamine hydrochloride and the whole thing is heated in the bath under a reflux condenser in about 3 hours. After the pyridine has evaporated, the residue is rubbed with dilute sodium hydroxide solution and extracted with ether. The ether extract is dried over an anthracite aqueous magnesium sulfate, sludge and sludge. The residue is recrystallized from methanol-heptane and ethanol - water and ethanol to give the title compound, mp 174-176 ° C.

Example XX. Oxime 4-14-diphenylmethylene piperidine / -4'-methoxybutyrophenone.

By repeating the procedure of example II but replacing 4'-bromo-4- [4- / 0 (-hydroxy a-fe- nylbenzyl / piperidine] butyrophenone with the appropriate amount of 4 - / - diphenylmethylene piperide hydrochloride- yno (3-methoxybutyrophenone) is obtained after recrystallization from a benzene-hexane mixture, the title compound in the free base form, mp 88-98 ° C.

Example XXI. 4'-fluoro-2- [4- (α-hydroxy-α-phenylbenzyl / piperidine] acetophenone oxime.

A mixture of 8 g (0.018 mol) 4'-fluoro-2- [4- (α-hydroxy-α-phenylbenzyl / piperidine] acetophenone, 70 ml ethanol and 70 ml of pyridine are heated under reflux for 3 hours with 2.5 g (0.036 mol) of hydrochloride. to hydroxylamine in 20 ml of ethanol. The reaction mixture is cooled to room temperature, poured into mixture of ice and water and, after diluting with water to the volume of about 1750 ml, leave overnight. Oil formed it is washed with water after the solvents have been decanted, dissolved in methylene chloride and dried over sulfate soda, soda and stasis. The residual oil is refluxed with 200 ml of hexane while adding a melt 75 ml of benzene at this time, then the supernatant is decanted and left overnight. Heating operations z hexane and benzene is repeated once more. The solution is sipped, after some time the compound is lost titanium, mp 157-161 ° C. *> 89 096 and itaw # go Mdli) laczrptBpflrng Lnumf

Claims (1)

1. Claim 1. Process for the preparation of new derivatives of substituted piperidine alkanone oximes of the general formula I, in which R is hydrogen or a hydroxyl radical, R1 is hydrogen or R and R1 together represent a second bond between carbon atoms, n is an integer with the value 1-3, Z represents a thienyl radical, a phenyl radical or a phenyl radical substituted in the ortho, meta or para position with a halogen atom, straight or branched lower alkyl group with 1-4 carbon atoms, lower alkoxy group with 1-4 carbon atoms, lower group dialkylamino or saturated monocyclic heterocyclic groups such as pyrrolidine, piperidine, morpholino, N-loweralkylpiperazine, optionally in the form of pharmaceutically acceptable salts thereof, characterized in that the compound of formula 6 wherein R, R1, n and Z are as defined above, react with the hydroxylamine salt in a solvent in the presence of a base for 1-8 hours at a temperature of up to 100 ° C. NH90H ^ X (CH2) n - c —z Formula 6 Formula 1 SCHEME 89 096 (CH2) n C — OH Formula 3 (CH2> n NOH II C — Z Formula 2 (CH2> n- NOH II C — Z W7Ór U NOH (CH0) - C — ZL n Formula 5 (CH2> n CZYf LLNIA Urzedo PoLe *